Paget’s disease of the bone is a chronic metabolic bone disorder that is characterized by focal areas of accelerated remodeling activity, which results in rapid bone resorption and excessive and disorganized bone formation.1

Aside from osteoporosis, Paget’s disease is the most common bone disorder. It is equally prevalent in men and women with an increased incidence in persons 50 years or older. It affects approximately 3 percent of persons in the United States, and as many as 10 percent of persons 80 years or older.3 It is important that as clinicians we have a better understanding of this disease for earlier detection, assessment and treatment.

Etiology

The etiology of Paget’s disease is largely unknown; however, some studies have provided support for both viral and hereditary causes. Viral antigens have been detected in affected osteoclasts. In the United States, the measles virus antigen is most commonly detected.3 Genetic studies have revealed that Sequestosome 1 (SQSTM1) is the most common gene associated with increased risk of Paget’s disease of the bone. Mutations of this gene were found in 20%-50% of familial cases and in about 5%-10% of sporadic cases.1 A positive family history is reported in as many as 40 percent of patients with Paget’s disease.3

The left femur shows bowing and trabecular and cortical thickening consistent with Paget’s disease.

Clinical Presentation

An estimated 70 percent of patients who have Paget’s disease have no symptoms. The disease can be silent until secondary abnormalities from progressive disease become apparent. Among those patients with symptoms, the most common complaint is poorly localized bone pain. The pain is typically described as constant, present at rest and worse at night.2 Symptoms are also largely dependent upon which area of the bone is affected. In the skull, bony enlargement can cause nerve compression leading to deafness. Bony deformity causing pressure on brain or spinal cord can cause headaches or vision loss.3 In the spine, bony deformity can cause symptoms related to spinal stenosis and/or radicular compression.2 If the jaw is involved, teeth may become loose. Studies have shown that the level of bone pain is directly proportionate to the level of disease activity.2

Diagnosis

The diagnosis of Paget’s disease is typically found incidentally on radiographs and laboratory investigations. Diagnosis can be suspected based on symptoms but radiographs are the most specific diagnostic test.3 Patient’s may complain of bone pain followed by joint pain due to secondary arthritis usually involving the knee, hip, or spine. The affected area may feel warm to palpation due to increased blood flow to the area. The characteristic feature seen radiographically includes coarsening of bone trabeculae with focal osteosclerosis, cortical thickening, and bone enlargement. Typical histology of the lesion reveals a mosaic of woven and lamellar bone, with the bone marrow being replaced by peritrabecular fibrosis and capillary ingrowth.1 There are many biochemical markers for Paget’s disease, but the one of the most important is serum alkaline phosphatase.3 Studies have measured the level of alkaline phosphatase, a marker of osteoblastic activity and found it to be correspondingly elevated during the bone formation and bone resorption phases of Paget’s disease. Measurements of alkaline phosphatase are used to assess the activity as well as monitor the effects of treatment.2 Bone scans can be used to increase the sensitivity in patients suspected of having Paget’s however it is less specific and should be interpreted cautiously.3 However the bone scan can be negative in the early osteolytic stages of Paget’s disease because of low metabolic activity and consequent decreased uptake of the radioisotope.2 Computed tomography and magnetic resonance imaging are not necessary.3

Medical Management

The most important indications for medical treatment of Paget’s disease are to relieve symptoms of bone pain and prevent complications resulting from unchecked destruction of healthy bone and abnormal overgrowth of pagetic bone.2 Other medical indicators for treatment include optimization of bone turnover to reduce vascularity in patients undergoing elective surgery such as joint arthroplasty. By decreasing the vascularity of the pagetic bone, this can reduce potential intraoperative blood loss.2 Also treatment for patients with skull or spine involvement which could potentially lead to deafness or spinal cord compromise.2 Treatment of Paget’s disease does not cure the disease but can provide prolonged periods of remission.3

Prior to 1975, there were many nonspecific treatments used to alleviate the manifestations of Paget’s disease; however, none were of true value. When salmon calcitonin was developed, there began a new era of effective treatment. Salmon calcitonin was the first calcitonin approved by regulatory agencies for the treatment of Paget’s disease.4 Administered as a subcutaneous injection of 50 to 100 IU daily, improvement of bone pain typically occurs within 2 to 3 weeks. A reduction in alkaline phosphatase which indicates decreased activity of the disease, can be seen in 3-6 months of treatment.2 Common side effects of calcitonin may include nausea, facial flushing, vomiting, abdominal pain, diarrhea, and polyuria. Although nasal spray calcitonin is less likely to cause these side effects, it is much less potent and therefore not a plausible option for treatment.4

The development of bisphosphonates for the treatment of skeletal disorders associated with increased bone resorption has been a major advancement in the management of Paget’s disease. The primary effect of bisphosphonates is to inhibit osteoclastic bone resorption, which is followed by a secondary decrease in bone formation.4 There are different modalities of bisphosphonate treatment administration, each with its own advantages and disadvantages.2 The oral bisphosphonates commonly used for treatment are alendronate and risedronate. Alendronate is generally dosed at 40mg daily for 6 months. Risedronate is dosed at 30mg daily for 2 months. Some of the stipulations that are associated with these medications are they must be taken on an empty stomach with 6-8 ounces of water. The patient must wait at least 30 minutes after taking these medications before eating any food, drinking anything other than tap water or taking any medication. The patient can not lie down for at least 30 minutes after taking the medication.4 Unfortunately this can affect patient compliance with treatment. Less commonly used oral bisphosphonates for treatment include etidronate and tiludronate.

In 1994, pamidronate was introduced as the first intravenous infusion for treatment of Paget’s disease. It is given as an IV infusion over 4 hours on 3 consecutive days. A single dose can also be effective in mild disease. A newer medication, zoledronic acid, is administered as a one-time IV dose and has been better for compliance. It was FDA approved for treatment in Pagets in 2007. A single infusion restores biochemical markers of bone turnover into the normal range and this is maintained for up to six and a half years in most patients.4 It can cause flu-like symptoms such as low-grade fever, myalgias, arthralgias or transient leukopenia that can persist for 2-3 days after the infusion. Patients should be forewarned about this however the symptoms are transient and self-limiting. This treatment has the potential to produce long remissions.

Summary

The identification and treatment of Paget’s disease of the bone has improved significantly over the last several decades. With continued advancements in molecular biology and genetics, we will continue to make strides in identifying and treating this disease, thereby reducing morbidity for those affected.

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